Method and apparatus for non-invasively determing a patients susceptibility to ventricular arrhythmias

ABSTRACT

A method and device for noninvasively determining a patient&#39;s susceptibility to ventricular arrhythmias is presented. The method is comprised of the steps of injecting small and safe amounts of electromagnetic energy into a patient and observing possible effects on the electrocardiogram or magnetocardiogram. The device is comprised of a means to inject small and safe amounts of electromagnetic energy into a patient, electrocardiogram or magnetocardiogram sensors connected to the patient, and means to display the signals of the electrocardiogram or magnetocardiogram sensors.

BACKGROUND OF THE INVENTION

Many individuals die every year from "cardiac electrical death". Thetypical sequence is that the person has a congenital electrical problemor undelying organic heart disease for years. This can suddenly causethe lower part of the heart ("ventricles") to race out of control(ventricular "tachycardia") with an inefficient excessive rate. Theventricular tachycardia can then rapidly deteriorate into an electricalstorm (ventricular "fibrillation") in which there is no pumping action.Unconsciousness occurs within 30 seconds and death follows in minutes.

There are three main therapies for such patients. The first therapy isantiarrhythmic drugs. Unfortunately, these have many side effects. Thesecond therapy is the implantation of a defibrillator. The implantabledefibrillator is designed to sense the ventricular tachycardia orventricular fibrillation and deliver appropriate pacing pulses or a highenergy defibrillation shock to the heart to restore normal ("sinus")rhythm. The third therapy is "ablation" in which the unstable heartcells, responsible for the arrhythmia, are destroyed through freezing orburning.

Because of the side effects of the drugs and the surgical risks involvedwith the implantable defibrillator or ablation therapy, patients areexamined very carefully before receiving their therapies. Theirpropensity for ventricular tachycardia or ventricular fibrillation isdetermined by attempting to "induce" one of these conditions. A currentcarrying catheter is introduced through the leg and one end is movedabout in the ventricle. Electrical pulses are then introduced into theventricle in an attempt to destabilize the heart. If either aventricular tachycardia or a ventricular fibrillation (collectivelyreferred to as a ventricular arrhythmia) occurs, the patient is said tobe "inducible" and the appropriate therapies are then prescribed.

The inducibility study is also referred to as an electorphysiologicalstudy or a PVS (programmed ventricular stimulation) study. While theinducibility study allows lifesaving therapies, it also has pain andrisks of death associated with it. Hence there is a need for anoninvasive and safe means of predicting inducibility.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a noninvasive and safemethod and device to predict inducibility.

It is known that passing very large direct current ("DC") continuous orDC pulsed currents through the patient's chest ("transthoracic"currents), on the order of 1 to 10 Amps can cause fibrillation. Smallertransthoracic pulsed currents, on the order of 100 mA, can pace theheart (control or "capture" the heart to the rate of the externalpulses).

Still smaller transthoracic currents, on the order of 10 mA, will nottypically interfere with the heart rhythm. A current of 1 mA alternatingcurrent (AC) is about the threshold of perception for the typicalindividual. Currents of 10μA to 100μA AC (depending on the organization)are considered totally safe to the human body for medical monitors byvarious standards and safety organizations. AC is much more dangerous tothe heart than is DC. For example, Underwriters Laboratory allowselectric fence currents of 5 mA (pulsed DC) but appliances are limitedto a leakage current of 500μA (60 Hz AC).

Patients that are inducible tend to have some heart ("myocardial") cellsthat are significantly less stable than normal. These cells are usuallyvery close to firing (triggering or "depolarizing") and may fire understressful conditions or even at random. That is the primary reason whythey can start a ventricular tachycardia and ventricular fibrillationand why the patient is inducible. A section of unstable cells causingventricular arrhythmias is referred to as an "ectopic focus".

A section of heart cells can also cause ventricular arrhythmias byoffering very slow passage of the pulse wave through their section. Thisslow passage can cause delays and inappropriate feedback which mayresult in a ventricular arrhythmia. This circular oscillation isreferred to as as "reentrant" ventricular arrhythmia.

Fortunately, the conditions that lead to cells being slow and allowingreentry also tend to make the cells unstable. Thus one primarily needsto test for instability to correctly predict inducibility.

Very small amounts of current through the heart may be sufficient tocause these "unstable" cells to depolarize, i.e. fire. By passing smalland safe amounts of electromagnetic energy through the patient's heartand noting small changes in the electrocardiogram (EKG) ormagnetocardiogram (MKG) it is possible to noninvasively detect theseunstable cells that could cause life threatening ventriculararrhythmias.

The heart can be stimulated and the heartbeat detected both by magneticand electric techniques. The electrical techniques will be discussed indetail here. The adaptation to magnetic techniques will be obvious tothose skilled in the art.

For maximum safety, this "microinduction" method and device begins withextremely small current pulses such as 100μA with a duration of 250μsec.These currents and duration may then be slowly increased with continuousmonitoring of EKG changes. If significant EKG changes are detected, thetest is terminated and end state results reported. If not, the pulsecurrents and/or durations are gradually increased until either changesare noted or a maximum safe level of stimulation is achieved.

For additional safety, the microinduction pulses are initiallypositioned in the safest part of the cardiac cycle, the "PR" segment.

Other objects, advantages, and novel features of the present inventionwill be apparent from the following detailed description when read inview of the appended claims and attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Listed by Figure Number

FIG. 1 is the transmembrane action potential of a healthy heart cell.

FIG. 2 shows the transmembrane action potentials of two "unstable" cellssuperimposed on that of a normal cell.

FIG. 3 is a normal skin surface EKG.

FIG. 4 shows the distribution of resting potentials in a normal heart.

FIG. 5 shows the distribution of resting potentials in a heart with someunstable cells.

FIG. 6 shows the effect of a small biasing current on the restingpotential distribution.

FIG. 7 shows the electrode connections on the front of the human body.

FIG. 8 shows the electrode connections on the human body for the Z-axiscurrent (front to back).

FIG. 9 shows the EKG with the delivery of a current pulse and theeffects of the pulse on an unstable heart.

FIG. 10 shows the voltage difference between the pulsed and control(unpulsed) EKG.

FIG. 11 shows the pulsed EKG for a Wedensky facilitation test with astimulus pulse located at the QRS onset.

FIG. 12 shows the pulsed EKG for a Wedensky facilitation test with a midQRS pulse location.

FIG. 13 is a flowchart listing detailed steps of the method.

FIG. 14 shows the dose response curves for an inducible and normalpatient.

FIG. 15 is a block diagram of the device.

FIG. 16 shows an alternative embodiment of the invention usingmagnetics.

FIG. 17 shows an alternative embodiment of the invention using a burstof high frequency stimulation.

FIG. 18 shows an alternative embodiment of the invention using acrescendo pulse train for stimulation.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The method of this invention can be understood by referring to FIG. 1.which shows a normal transmembrane action potential or simply "actionpotential". This is the voltage ("potential") difference between theinside and outside (hence "transmembrane") of an individual heart cellwhen it fires or triggers (hence "action"). The lower line 1 shows the"resting potential" or voltage that the cell assumes between firings. Itis also referred to as the "polarized" or "repolarized" voltage. Atypical value is -85 mV. The rising line 2 represents the first stage("onset") of the firing of the cell. A typical value for the slope is300 V/S. The peak voltage attained is about 25 mV. There is a plateauregion of mostly positive voltage 3 and a return (to resting) process ofthe cell (repolarization) 4. The total time that the cell is fired iscalled the potential duration time 5.

The cell has a firing threshold level 6 of approximately -60 mV. Whenthis voltage is achieved, due to a combination of internal or external(mostly external) processes, the cell proceeds inexorably towards andthrough a complete firing cycle.

FIG. 2 shows the action potential of two abnormal cells superimposed ona normal action potential. Note that the resting potential is much lessnegative, the onset slew rate is diminished, and the plateau voltagesare reduced. The potential duration is reduced in one cell but isincreased in the other. Both can occur.

FIG. 3 shows the skin surface electrocardiogram (EKG) of an adult human.The first rounded deflection 7 is the P wave and represents the topchambers (atria) of the heart firing to prefill the ventricles for themain pumping action of the heart. The P wave is rather small as thereare comparatively few cells firing.

The most pronounced feature of the EKG is the QRS complex. Thisrepresents the firing of the ventricles. It is caused by the collectivecurrent generated by the cells going through the onset of their actionpotentials. The first downward deflection is called the Q wave 8. Thefirst upward deflection is the R wave 9. The trailing downwarddeflection is the S wave 10. When one is merely trying to differentiatebetween the QRS complex and, say, the P or T waves, the QRS complex isoften referred to merely and the "R wave."

The final rounded feature of the EKG is the T wave 11. This representsthe repolarization of the ventricular cells and hence the collectivecurrents of the cells going through their repolarization transitions.

The time between the P wave and QRS complex is called the PR interval12. The voltage line between the QRS complex and the T wave is calledthe ST segment 13.

FIG. 4 shows a probability distribution (fine-grained histogram) of theresting potentials of the ventricular cells in a healthy heart. Themeans and mode 14 are both at approximately -85 mV. Note that the 99thpercentile point 15 is well away from the threshold voltage 16. In otherwords, the cells in a healthy heart are (electrically) far away fromfiring.

FIG. 5 shows the probability distribution of the resting potentials ofthe ventricular cells in a diseased heart. Note that the mode 17 isstill at approximately -85 mV. Because some of the venticular cells haveless negative (or "decreased") resting potentials, the overalldistribution is no longer symmetrical and Gaussian. It is now skewed andmay even be bimodal with a more positive secondary mode 18. The medianresting potential 19 is now slightly more positive. Of criticalimportance is the fact that the 99th percentile is now much closer tothe threshold voltage.

FIg. 6 shows the possible effect of a biasing current through the heart.A current, in the right direction, may decrease (make less polarized,i.e. more positive) the resting potential of a cell. With theappropriate current through the heart, there will be a voltage gradientand the probability distribution of the resting potentials will beshifted up. Here the median resting potential is no longer -85 mV. Thosecells, 20 in a diseased heart, whose resting potentials were alreadyclose to the threshold voltage, may now be shifted over the threshold.The cells would, of course, fire immediately and thus this section ofthe probability distribution represents a very transient situation.

FIG. 7 shows the electrode positions for introducing the low biasingcurrent into the patent's chest. Electrodes XR 21 and XL 22 are used todrive a horizontal or "transverse" current across the chest. They arealternately given the positive polarity (left to right or right to left)to maximize the total number of cells that experience biasing.Electrodes YU 23 and YL 24 are used to drive a largely vertical currentthrough the chest. Again, their polarities are alternated. Sensingelectrodes are in the traditional (12-lead) positions or in additionalphysician selected positions and are not shown here.

FIG. 8 shows the electrode positions for introducing the low biasingcurrent directly through the patient's chest from the front to back andvice-versa. Electrodes ZB 25 and ZF 26 are used to drive this "Z-axis"current through the chest.

FIG. 9 shows the biasing current pulse 27 in its time position on theEKG with an idealized response of a diseased heart. The changes to theEKG shown here are very exaggerated as the actual effects of the biasingpulse would not typically be visible to the human eye. The first changeshown in an immediate response to the biasing pulse. In this case, cellsthat were near the threshold fired immediately after the pulse producinga small deflection 28. The next change is in the QRS complex 29 andrepresents the loss of contribution of those earlier firing cells whichwould have normally contributed to the R wave.

When the pre-stimulated cells repolarize, they again affect the EKG.First, their repolarization occurs earlier than the T wave and thus cancause a deflection in the ST segment 30. The next change is in the Twave itself 31 and represents the loss of repolarization contribution ofthose earlier firing cells which would have normally contributed to theT wave.

FIG. 10 shows the algebraic difference between the conventional(passive) EKG of FIG. 3 and the biased EKG of FIG. 9. One of thesedifference waveforms is calculated, displayed, and printed for eachcombination of sensing electrode, current, pulse duration, biasingorientation (horizontal or vertical), and biasing polarity (top or leftor back electrode positive vs. bottom or right or left electrodepositive). This waveform is averaged for many cycles and the integratedabsolute voltage difference of the averages is reported as a measure ofcardiac instability. This value is called the "early potential measure"and is given by: ##EQU1## where the integral is given over the cardiaccycle from one P wave to the next with blanking during the actualstimulation pulse time. "E" is the EKG voltage with respect to time. Themodulo 4 summation indices refer to the fact that the stimulationchanges every 4 cardiac cycles from positive, zero, negative, andfinally back to zero. The choice of 16 cycles for averaging is somewhatarbitrary. The operator can choose any number and thus select areasonable compromise between patient convenience and noise rejection.

FIG. 11 shows the possible effect of a biasing current pulse at the QRSonset 32. All of the changes shown in FIG. 9 are still possible but areleft off of this figure for clarity. Another effect is emphasized herewhich is slightly different in principal from the directly stimulatedearly potentials. The stimulation of the biasing current pulse may nothave been strong enough, on its own, to have caused the unstable cellsto fire as was shown in FIG. 9. However, the earlier partial("subthreshold") stimulation may increase the sensitivity of a cell sothat it fires earlier in the cardiac cycle than it normally would. Anincrease in sensitivity of a neurological cell due to a shortly earliersubthreshold stimulation is called a Wedensky facilitation.

The Wedensky facilitation may cause an unstable cell that was normallytriggered by the electrical wave going through the heart to fire whilethe wave is some distance away because of the increased sensitivity. Ifthere were any unstable cells, this would cause a shift of some of theenergy of the QRS complex towards the first stages. This would cause adistortion in the early part of the QRS 33 with a compensatory andopposite distortion in a later region 34.

A similar effect can occur in the T wave. This figure also shows adistortion in the early part of the T wave 35 with a compensatory andopposite distortion in a later region 36.

Refer now to FIG. 12. The Wedensky facilitation last for about 50 mSecafter the subthreshold stimulation pulse. Thus to cover the QRS complex(which is nearly 100 mSec wide) one needs to stimulate again in thecenter of the R wave 37. Also shown is a distortion in the late part ofthe QRS 38 from cells that are now able to fire earlier. The dottedsignal in the S wave area represents abnormal cells that had such a slowresponse that their firing did not usually occur until after the main Rwave activation 39. These "late potentials" are often seen withaveraging in conventional passive EKGs. With the Wedensky facilitationfrom the biasing current pulse these cells will tend to fire duringtheir appropriate time and thus there will be a decrease in the latepotential region. This activity will tend to shift ahead into a part ofthe QRS more closely following the stimulus pulse.

As mentioned in the Summary, slow conduction can be a cause ofventricular arrhythmias. With the use of a Wedensky facilitationstimulation, the slower responding cells can be detected. The differencewaveforms and integrated voltage difference measure are calculated justas they are for the early potentials as shown in Eq. 1.

Thus the bias pulsed waveform (e.g. FIG. 9) and the difference waveform(e.g. FIG. 10) can be fairly complicated. However, the integratedvoltage calculation of the difference waveform will include thecontributions of the various shifts and hence give a measure of thetotal level of cardiac instability for both the early potential test andthe early (QRS onset) and mid QRS stimulation test.

FIG. 13 is a flow chart of the method. The operator selects a stimulustemporal location of PR interval, QRS onset, mid-QRS, or even theST-segment of T wave 40. The test begins with a minimal energy biasingcurrent pulse of approximately 100 μA and a width of approximately 250μsec 41. The orientation is first set at vertical which means that thecurrent flows through the electrodes YU and YL. The orientation is thenalternated to transverse for the next pass through the procedure 42.Finally, if the operator desires, a Z-axis pass is made.

For each orientation and biasing current pulse energy level, the biasingcycle is repeated approximately 16 times to allow for signal averagingfor noise reduction 43.

The basic innermost cycle involves a positive biasing current pulse, azero bias cycle, a negative bias cycle, and a zero bias cycle 44. If aPVC is caused by the biasing, the system automatically "rests" for 10cardiac cycles for safety 45. If, however, a total of 5 PVCs aregenerated then the test is terminated.

For each combination of sensing electrode, current, pulse duration,biasing orientation (transverse, vertical, or Z-axis), and biasingpolarity (top or left or back electrode positive vs. bottom or right orfront electrode positive) the resulting (averaged) waveform anddifference waveform are displayed and printed 46. The integrated voltageof the absolute value of the average difference is reported as a measureof cardiac instability by Eq. 1.

A cross-correlation is calculated between the stimulus and thedifference waveform. As is well known in the art of signal processing,the peaks of the cross-correlation function then show how much delayexists between the stimulus and the response. This gives an estimate ofthe response speed of the abnormal cells which is valuable for theclassification of the abnormal cells.

An auto-correlation is calculated of the response (with itself). As iswell known in the art of signal processing, auto-correlation finds timedelays between similar portions of the same signal. This will estimatethe time between the depolarization and repolarization of the abnormalcells. This time is the potential duration and is valuable forclassifying these abnormal cells.

A frequency spectrum is calculated of both the averaged QRS complex andthe averaged difference waveform response. The median frequency iscalculated for each. The ratio of the median frequencies is calculated.As is well known in the art of electrical engineering, the slew rate ofa pulse edge is directly proportional to its frequency content. Thisestimates the relative ratios of the slopes of the firing of theabnormal cells to the normal cells. As slow responding cells areespecially capable of causing ventricular arrhythmias this informationis valuable for the diagnosing physician.

The pulse energy is then increased one step and the process is continueduntil the safety maximum is reached 47. At that point, the process maybe reversed, at operator option, and the biasing current pulse energy issteadily decreased until the starting minimums are reached. Thephysician can thus compare ascending values to descending values tocheck for hysteresis phenomena.

FIG. 14 shows two dose response curves for the early potential measure(EPM) versus the biasing current pulse strength for a fixed width of 10mSec. The top curve is for an inducible patient 48. Note that the EPMfirst moves up from the noise floor at a small current while the normalpatient's curve remains at the noise floor 49. Of course, if the pulsecurrent were increased substantially beyond the safety limits of 10 mA50 then pacing would occur and the EPM would grow very large for eitherpatient.

FIG. 15 is a block diagram of the device. A small work station (or highperformance personal computer) 51 is connected to a digital to analogconverter 52 to generate pulses of the proper timing and voltage. Thesepulses are then fed into a floating current converter 53 which generatesa differential current which is then fed into the orientation selectingrelays 54. These relays (also under computer control) select theelectrodes 55 to receive the biasing current pulse.

Sensing electrodes 56 deliver the patient's EKG signals to a voltage andcurrent limiter 57. The signals then go through an amplifier, 58 ananalog to digital converter, 59 and finally into the work station foranalysis.

FIG. 16 shows an alternative embodiment of the invention. Here, magnets60 deliver the stimulating energy and a magnetic sensor 61 detects theresponse. The advantage of this embodiment is that the patient does notneed electrode preparation (such as shaving) and application. A furtheradvantage is that, with multiple magnetic sensors, it is possible to doimaging and thus one could image the response of the unstable cells. Adisadvantage is that the magnets and magnetic sensors are expensive.Hybrid approaches are possible. For example, one could use magneticstimulation and the electrical sensing shown in FIG. 15 and vice versa.Similarly the stimulating magnets drawn could actually represent largecapacitive plates which would stimulate through capacitive(electrostatic) coupling. Sensing would be either magnetic or conductive(through electrodes).

FIG. 17 depicts another alternative embodiment of the invention. Here aburst of higher frequency stimulation 62 is placed in the PR interval.It could just as well be placed in the QRS complex. Through thetechnique of synchronous demodulation (well known in the art of signalprocessing) the stimulation signal itself can be removed from the EKGsignal. The advantage of this approach is that the response can be seenand voltage difference integrated throughout the cardiac cycle withoutconfusion with the stimulation itself. A disadvantage is that thecardiac cells do not respond strongly to very high frequencies.

FIG. 18 shows another alternative embodiment of the invention. Here acrescendo train of pulses 63 is used for stimulation. A burst of higherfrequency such as that shown in FIG. 17 can also be used with crescendomodulation. Synchronous demodulation is again used to separate thestimulus from its result. With the amplitude rising with everyindividual stimulus pulse, the EKG response is checked in between. If avoltage response over 100μ V is sensed, then it is suspected of being aPVC and the stimulation level is frozen or the test returns to a normalprocedure as shown in FIG. 13. The advantage of this approach is thatthe test can be run much more rapidly since many increments can be madein one cardiac cycle. The disadvantage is that the responses may notfully develop between pulses and thus the accuracy may suffer.

It is preferred, for safety reasons, that the biasing current pulseoccur in the PR interval or QRS complex. With sufficient strength thebiasing current pulse could enlist enough cells so that a cascade occursand the ventricles fire before the normal time. This is called apremature ventricular complex (PVC). The average person may have severalPVCs during the day and they are not considered dangerous at that level.If the biasing current pulse were to cause a PVC in the PR interval, theheart would merely contract slightly earlier with slightly lessefficiency. There is also no danger in the QRS since the heart isalready firing. If, however, PVCs were to occur repeatedly in the middleof the T wave, ventricular tachycardia could occur. Hence it ispreferred to deliver the biasing current pulses in the PR interval andQRS complex.

Biasing current pulses could, however, be delivered later in the cardiaccycle to measure such parameters as recovery and refractoriness(receptiveness to another pulse). The system would have to diligentlymonitor the heart's responses.

As an alternative embodiment, the stimulus pulse could be placed in themiddle of the T wave and the response tested. The advantage of thisembodiment is that it closely mimics the timing of invasive inducibilitystudies. A disadvantage is that it has a risk of fibrillation with asufficiently strong pulse.

As an alternative embodiment, the stimulus pulse could be of a largerstrength of approximately 100mA and 10mSec wide. An advantage of thisembodiment is that it would completely capture the heart (pace) and thechanges to the EKG would be much more dramatic. A further advantage isthat the pulse (or multiple pulses) could be placed in or after the Twave and thus more closely mimic the approach of invasive inducibilitystudies. A disadvantage is that it has a risk of fibrillation with asufficiently strong pulse.

As an alternative embodiment, the stimulus pulse could be very wide,such as approximately 100mSec in order to completely cover the R wave.An advantage of this embodiment is that it would have a betteropportunity of stimulating all ventricular cells. A disadvantage is thatit is more difficult to separate the pulse signal from the patient's EKGsignal.

As an alternative embodiment, the device could have the capability ofdelivering regularly spaced high strength pulses to restore the heart toa normal rhythm. This technique is known as "overdrive pacing" and isused to recapture the heart from ventricular tachycardia. An advantageof this embodiment is that it would allow for restoration of normalrhythm in case ventricular tachyardia occurred. A disadvantage is thatit requires more electronic hardware and could require more operatortraining.

As an alternative embodiment, the device could have the capability ofvarying the location of the stimulus pulse until it found a maximalresponse. It would then continue to pulse in this timing location. Anadvantage of this embodiment is that it would allow better signal tonoise ratios in the signal. A disadvantage is that it could make patientto patient comparisons more difficult and decrease repeatability.

We claim:
 1. A device for determining a patient's susceptibility toventricular arrhythmias, comprising:a. means to inject electromagneticenergy into a patient's body with pulses of less than 100 milliamperesof current; b. at least two electrocardiographic leads connected to apatient's body to detect electrocardiographic signals; and, c. meansconnected to the means to inject and to the at least two leads to recordthe changes in the patient's electrocardiographic signals caused by theinjection of the electromagnetic energy;thereby sensing the cardiacinstability related to ventricular arrhythmias noninvasively .
 2. Thedevice of claim 1, wherein said means to inject is at least twoelectrodes wherein the electromagnetic energy is injected into the bodyas an electrical current through the electrodes said electrical currentgenerated by electronic means synchronized to the heart beat.
 3. Thedevice of claim 1, wherein the amount of electromagnetic energy ismaintained below the level which would pace a patient's heart byimmediately pausing the energy delivery if any pacing occurs.
 4. Amethod for determining a patient's susceptibility to ventriculararrhythmias, comprising the steps of :a. injecting electromagneticenergy into a patient's body with pulses of less than 100 milliamperesof current; b. monitoring electrocardiographic signals from at least twoelectrocardiographic leads connected to the patient's body; and, c.recording the changes in the patient's electrocardiographic signalscaused by the injection of the electromagnetic energy;thereby sensingthe cardiac instability related to ventricular arrhythmias noninvasively.
 5. The method of claim 4, wherein the step of injecting theelectromagnetic energy into the body is performed by passing anelectrical current through electrodes on the patient's body.
 6. Themethod of claim 4, wherein the amount of electromagnetic energy ismaintained below the level which would pace the patient's heart byimmediately pausing the energy delivery if any pacing occurs.